Abstract: SA-OR50
Crescents Derive from Single Podocyte Progenitors and a Drug Enhancing Their Differentiation Attenuates Rapidly Progressive Glomerulonephritis
Session Information
- Assessing Disease Risk in Children: A Developmental Perspective
November 06, 2021 | Location: Simulive, Virtual Only
Abstract Time: 04:30 PM - 06:00 PM
Category: Development, Stem Cells, and Regenerative Medicine
- 500 Development, Stem Cells, and Regenerative Medicine
Authors
- Melica, Maria elena, Universita degli Studi di Firenze, Firenze, Toscana, Italy
- Antonelli, Giulia, Universita degli Studi di Firenze, Firenze, Toscana, Italy
- Angelotti, Maria Lucia, Universita degli Studi di Firenze, Firenze, Toscana, Italy
- Lugli, Gianmarco, Universita degli Studi di Firenze, Firenze, Toscana, Italy
- Conte, Carolina, Universita degli Studi di Firenze, Firenze, Toscana, Italy
- De Chiara, Letizia, Universita degli Studi di Firenze, Firenze, Toscana, Italy
- Ravaglia, Fiammetta, Universita degli Studi di Firenze, Firenze, Toscana, Italy
- Peired, Anna Julie, Universita degli Studi di Firenze, Firenze, Toscana, Italy
- Mazzinghi, Benedetta, Universita degli Studi di Firenze, Firenze, Toscana, Italy
- Lazzeri, Elena, Universita degli Studi di Firenze, Firenze, Toscana, Italy
- Semeraro, Roberto, Universita degli Studi di Firenze, Firenze, Toscana, Italy
- Lasagni, Laura, Universita degli Studi di Firenze, Firenze, Toscana, Italy
- Romagnani, Paola, Universita degli Studi di Firenze, Firenze, Toscana, Italy
Background
Rapidly progressive glomerulonephritis (RPGN) is characterized by crescent formation, which typically, is the consequence of diverse upstream pathomechanisms involving the specific activation of PEC,represente which represent in part renal progenitor cells (RPC). Similarities with stem cell of bone marrow prompted us to hypothesized that crescents result from clonal expansion of a single RPC, conceptually similar to monoclonal diseases originating from hematopoietic stem cells. We further hypothesized that drugs known to cure hematopoietic disease by enforcing their terminal differentiation could also attenuate crescentic glomerulonephritis.
Methods
We established a RPGN disease model in a conditional transgenic mouse based on the mT/mG and the Confetti reporter that allows lineage tracing of RPC.Mice were treated with drugs currently used in myeloproliferative disorders. Crescentic lesions were characterized by super-resolution STED microscopy.Single cell RNA sequencing of human renal progenitor cultures identify the immature progenitor subset-generating crescent in human.
Results
We observed that crescents originated from the clonal expansion of single RPC, thus suggesting a clonal stem cell disorder. Therefore, we administrated a series of drugs known to ameliorates myeloproliferative neoplasms to our mouse model. Treatment with one of the compounds induced a reduction in both proteinuria and crescent formation. 3D confocal microscopy and STED super-resolution imaging of glomeruli showed that this compound turned the uncontrolled hyperplasia of a immature PEC subset into a controlled differentiation into new podocytes restoring the injured glomerular filtration barrier.
Single cell RNA of human renal progenitor cultures identified a new marker of the crescent-generating progenitor cells. Expression of this marker in biopsies of patients with RPGN associated with progression toward end stage kidney disease.
Conclusion
These results demonstrate that glomerular hyperplastic lesions derive from clonal amplification of a RPC subset and that shifting proliferation to podocyte differentiation reverses crescent formation and improves clinical outcome.